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Originally published as JCO Early Release 10.1200/JCO.2009.25.4078 on November 2 2009 © 2009 American Society of Clinical Oncology.
Cardiovascular Disease With Androgen Deprivation: The (forgotten) Role of TestosteroneGeorge Washington University Medical Center, Washington, DC To the Editor: Alibhai et al1 presented significant data regarding cardiovascular and diabetic morbidity results in men 66 years of age or older undergoing androgen deprivation therapy (ADT), in which they found an increased risk of diabetes and fragility fracture but not acute myocardial infarction (MI) or sudden cardiac death. This report is consistent with that of some studies, such as the nonstatistically significant risk of cardiovascular mortality in men with localized prostate cancer undergoing ADT in Radiation Therapy Oncology Group (RTOG) 92-02,2 RTOG 86-10,3 and RTOG 85-31,4 but contrary to other studies which have reported that ADT as short as 3 months could impact men older than 65 years with increased fatal cardiovascular events.5,6 The effects of ADT on cardiovascular disease and risk factors are not new, yet time and again, we see conflicting results regarding this basic question. While the differences may be explained by the retrospective nature or the differences in population number, as suggested by the authors, this study did not take into consideration one of the basic observations regarding baseline cardiovascular risk in older men, that is, lower testosterone levels with increasing age. Of the contemporary causes of death among all American men age 65 or older, heart disease is still the leading cause with an incidence of about 30.5%, compared with cancer, at 25.4%.7 While there are certainly controllable risk factors, such as hypertension, diabetes, smoking, which Alibhai et al's study controlled for in their analysis, certain unknown risk factors come into play that could result in increased risk of sudden cardiac death. In Alibhai et al's study, which comprises of the most patients compared with other studies that have evaluated cardiovascular risk in those undergoing ADT, no increased risk of sudden cardiac death or MI was concluded. One of the data which could be useful, though not available, is the testosterone data. Hypogonadism has been recognized to increase in prevalence with increased age. The incidence is approximately 20% for men older than 60, 30% in men older than 70, and up to 50% in men older than 80 years.8 Hypogonadism has been associated with increased cardiovascular risk. In a study by Khaw et al,9 men with testosterone levels of at least 19.6 nmol/L had a 41% lower risk of dying in 10 years compared with men who had testosterone levels of 12.5 nmol/L or less and for every 6-nmol/L increase in endogenous testosterone, the risk of death decreased 14%. While ADT certainly suppresses further the degree of hypogonadism, studies on testosterone kinetics after 6 months of ADT would lead to testosterone recovery at a median of 15.4 weeks.10 However, in this study, no data was specifically available regarding the specific number of patients who underwent specific duration of ADT therapy. While categorization of fewer than 3 months, 3 to 6 months, 6 to 24 months, and longer than 24 months does prove useful and simplifies analysis, these duration stratification can have variable effect on testosterone recovery. In addition, we have previously shown that factors such as age older than 67 years, for instance, take even a longer time to testosterone recovery.10 This could perhaps account for the nonstatistical differences that were observed, given that the analysis was limited to men older than 65 years. In fact, as D'Amico et al's5 study showed for instance, men younger than 65 years had too few cardiovascular events observed that it was insufficent to compare the effects of ADT duration to time to a fatal MI, suggesting the hypothesis on testosterone effects and the role it plays on cardiovascular mortality. While Alibhai et al showed the total number of ADT users versus nonusers as well as the multivariate Cox proportional hazard ratios between different ADT use at specified time points, information on exact number of patients developing specific events was not clearly depicted in the article, thereby possibly over- or underestimating the incidence. Alibhai et al's analysis make up the largest study with evaluable patients on ADT to date, and while it is comforting that no significant risks of cardiovascular mortality is seen in their analysis, an increasing number of physicians and patients alike, are still awaiting the final verdict to settle the issue of what the fate of ADT would be, in the treatment of varying stages and risk-features in prostate cancer in light of the touted increased cardiovascular risk and mortality. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Alibhai SM, Duong-Hua M, Sutradhar R, et al: Impact of androgen deprivation therapy on cardiovascular disease and diabetes. J Clin Oncol 27:3452–3458, 2009. 2. Efstathiou JA, Bae K, Shipley WU, et al: Cardiovascular mortality and duration of androgen deprivation for locally advanced prostate cancer: Analysis of RTOG 92–02. Eur Urol 54:816–823, 2008.[CrossRef][Medline] 3. Roach M III, Bae K, Speight J, et al: Short-term neoadjuvant androgen deprivation therapy and external-beam radiotherapy for locally advanced prostate cancer: Long-term results of RTOG 8610. J Clin Oncol 26:585–591, 2008. 4. Efstathiou JA, Bae K, Shipley WU, et al: Cardiovascular mortality after androgen deprivation therapy for locally advanced prostate cancer: RTOG 85–31. J Clin Oncol 27:92–99, 2009. 5. D'Amico AV, Denham JW, Crook J, et al: Influence of androgen suppression therapy for prostate cancer on the frequency and timing of fatal myocardial infarctions. J Clin Oncol 25:2420–2425, 2007. 6. Tsai HK, D'Amico AV, Sadetsky N, et al: Androgen deprivation therapy for localized prostate cancer and the risk of cardiovascular mortality. J Natl Cancer Inst 99:1516–1524, 2007. 7. Centers for Disease Control. Leading Causes of Death by Age Group, All Males - United States, 2004. http//www.cdc.gov/men/lcod/04all.pdf. 8. Liu PP, Fukuoka M: Sex hormones as novel risk biomarkers for atherosclerosis in peripheral vascular disease. J Am Coll Cardiol 50:1077–1079, 2007. 9. Khaw KT, Dowsett M, Folkerd E, et al: Endogenous testosterone and mortality due to all causes, cardiovascular disease, and cancer in men: European prospective investigation into cancer in Norfolk (EPIC-Norfolk) Prospective Population Study. Circulation 116:2694–2701, 2007. 10. Gulley JL, Aragon-Ching JB, Steinberg SM, et al: Kinetics of serum androgen normalization and factors associated with testosterone reserve after limited androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 180:1432–1437, 2008 discussion 1437, 2008.[CrossRef][Medline]
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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